GATA2 Haploinsufficiency Caused by Mutations in a Conserved Intronic Element Leads to MonoMAC Syndrome

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2013 Mar 19

PMID 23502222

Citations 135

Authors

Amy P Hsu

Kirby D Johnson

E Liana Falcone

Rajendran Sanalkumar

Lauren Sanchez

Dennis D Hickstein

Jennifer Cuellar-Rodriguez

Jacob E Lemieux

Christa S Zerbe

Emery H Bresnick

Steven M Holland

Affiliations

Soon will be listed here.

Abstract

Previous reports of GATA2 mutations have focused on the coding region of the gene or full gene deletions. We recently identified 2 patients with novel insertion/deletion mutations predicted to result in mRNA nonsense-mediated decay, suggesting haploinsufficiency as the mechanism of GATA2 deficient disease. We therefore screened patients without identified exonic lesions for mutations within conserved noncoding and intronic regions. We discovered 1 patient with an intronic deletion mutation, 4 patients with point mutations within a conserved intronic element, and 3 patients with reduced or absent transcription from 1 allele. All mutations affected GATA2 transcription. Full-length cDNA analysis provided evidence for decreased expression of the mutant alleles. The intronic deletion and point mutations considerably reduced the enhancer activity of the intron 5 enhancer. Analysis of 512 immune system genes revealed similar expression profiles in all clinically affected patients and reduced GATA2 transcript levels. These mutations strongly support the haploinsufficient nature of GATA2 deficiency and identify transcriptional mechanisms and targets that lead to MonoMAC syndrome.

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